Diabetes mellitus is characterized by abnormal plasma glucose level. There are more than 16 millions patients with diabetes mellitus in the United States. Among them, 90-95% are type 2 diabetes, which is characterized by insulin resistance and relative insulin deficiency. It is a serious health problem. Health care costs related to diabetes are over $100 billions/year in the United States.
Current treatment for type 2 diabetes includes oral glucose-lowering agents and insulin. There are four major classes of oral glucose lowering agents, including biguanides (e.g., metformin), sulfonylureas (e.g., glyburide), thiazolidinediones and alpha-glucosidase inhibitors. As the recent understanding of the importance of normalizing plasma glucose to prevent the development of diabetic complications, the magnitude of the glucose-lowering effect with monotherapy is often not satisfactory. There has been a trend to combine agents from different classes to achieve better glucose control. One example is Glucovance (Bristol-Myers Squibb), which is a combination of metformin and glyburide, two commonly use oral glucose-lowering agents.
Type 2 diabetes is a complicated disease. In addition to elevated plasma glucose concentration, other abnormalities also involve in the development of complications. Most of patients with type 2 diabetes are dyslipidemic, as characterized by high triglycerides, small dense LDL (Low Density Lipoprotein), LDL-cholesterol and low HDL (High Density Lipoprotein)-cholesterol. These abnormalities obviously contribute to the development of cardiovascular complications. None of the current oral glucose-lowering agents satisfactorily improve dyslipidemia, nor do the combination of these agents. There is a need for better control of hyperglycemia and improving dyslipidemia at the same time.
Metformin is a member of biguanides. It has been widely used in the treatment of type 2 diabetes. It reduces elevated plasma glucose concentrations, mainly by suppressing hepatic glucose output. Other members of biguanides include phenformin and buformin.
Gemfibrozil and ciprofibrate belong to the fibrate family, a class of agent indicated for improving lipid levels. Other fibrates include clofibrate, fenofibrate and bezofibrate. These agents reduce hypertriglyceridaemia and hypercholesterolaemia. More importantly, their properties on elevating HDL-cholesterol and reducing small dense LDL are highly appreciated recently because circulating low HDL cholesterol and high small dense LDL are highly atherogenic in patients with type 2 diabetes. Among the fibrates, some, including fenofibrate and bezafibrate, possess some degree of glucose-lowering effect (WO 99/40904 and U.S. Pat. No. 5,304,575), while the others including clofibrate, gemfibrozil and ciprofibrate are lack of glucose-lowering effect (WO99/40904; Vuorinen-Markkola H et al. Diabetologia 1993, 36:161-9; Hernandez-Mijares A et al. Nutr Metab Cardiovasc Dis 2000, 10:1-6). As such, fibrates can be sub-divided into “glucose-lowering fibrates” and “non-glucose-lowering fibrates”. A non-glucose-lowering fibrate is a fibrate that does not have statistically significant glucose lowering effect when used alone.
The combination of a hypoglycemic agent and a lipid-improving agent has already been envisaged in the art, especially for treating diabetic patients with severe hypertriglyceridaemia and hypercholesterolaemia. However, these combinations have been in the context of using respective agents to correct respective abnormalities, not anticipating additional benefits from the combinations. In fact, contradictory results were obtained depending on the drugs used in the combination. Combination of metformin and members of non-glucose-lowering fibrate, such as clofibrate has failed to show better control of hyperglycemia (WO 99/40904). On the other hand, combination of metformin and members of glucose-lowering fibrate, such as fenofibrate and bezafibrate, led to better control of hyperglycemia (WO99/40904), although this was not a synergistic effect. It was the outcome of an additive glucose-lowering effect of metformin and these fibrates, since synergism is defined as the joint action of agents so that their combined effects is greater than the algebraic sum of their individual effects (Dorland's Illustrated Medical Dictionary, 27th Edition). From these examples, it is obvious to a person in skill of art that better hyperglycemic control can be obtained when combining the use of metformin and a glucose-lowering fibrate, while better hyperglycemic control can not be obtained when combining the use of metformin and a non-glucose-lowering fibrate.
Surprisingly, the current inventor discovered that combined administration of metformin and gemfibrozil or ciprofibrate, two members of the non-glucose-lowering fibrates, produced an unexpected synergistic reduction of plasma glucose concentrations.